DESCRIPTION (Applicant's Abstract): Clozapine is more effective for negative symptoms of schizophrenia than conventional neuroleptics, but the neurochemical actions contributing to this superior clinical efficacy remain unclear. Recent evidence points to a role for glutamatergic dysregulation in schizophrenia, as well as important differences between conventional agents and clozapine in effects upon glutamatergic systems. We have shown that D-cycloserine, a partial agonist at the glycine modulatory site of the NMDA receptor, improves negative symptoms when added to conventional agents and worsens negative symptoms when added to clozapine. Another group has demonstrated that high-dose glycine also improves negative symptoms and has provided preliminary evidence suggesting that glycine improves negative symptoms when added to clozapine. Serum concentrations of glycine predicted response to both high-dose glycine and D-cycloserine. These findings led us to the hypothesis that both clozapine and D-cycloserine improve negative symptoms by activation of the glycine modulatory site of the NMDA receptor complex. Because D-cycloserine is a partial agonist, it may act as an antagonist at the glycine site in the presence of clozapine, whereas the full agonist, glycine, would not be expected to worsen negative symptoms in the presence of clozapine. We now propose a placebo-controlled, parallel-group, eight-week, fixed-dose trial of D-cycloserine 50 mg/d and glycine 60 gm/d added to clozapine in 45 patients with schizophrenia. We hypothesize that glycine will produce improvement in negative symptoms and D-cycloserine will produce worsening compared to placebo. We will also determine whether cerebrospinal fluid concentrations of glycine and other relevant amino acids predict response and will measure effects of D-cycloserine and glycine on serum amino acid concentrations. Because assessments are standardized between studies, results from this study can be compared with results from our study of D-cycloserine added to conventional neuroleptic (R01 MH54245).